JPS6187681A - 1,3-dimethyl-1h-purine-2,6-diones containing 1h-indol-3-yl, manufacture and use - Google Patents

Abstract

1H-indol-3-yl containing 1,3-dimethyl-1H-purine-2,6-diones of the formula <CHEM> and the pharmaceutically acceptable acid addition salts thereof, which compounds have sedating, anxiolytic, anti-aggressive and anti-stress activities; pharmaceutical compositions comprising such compounds as active ingredients and processes of preparing such compounds and pharmaceutical compositions.

Description

DETAILED DESCRIPTION OF THE INVENTION In European Patent No. 71,738, a number of bi4lisone and biberasone-containing theophylline derivatives are described as compounds with various pharmacological activities.

Additionally, many 4-[1#-indole-3-ylcopiperidines are described in U.S. Pat. and antiallergic and hypotensive agents and serotonin antagonists, respectively.
nists) in U.S. Pat. Nos. 4,359,468 and 4,342,870. The compounds of the present invention are viverison or 3,6-sohydro-1(
1,3-tmethyl-1H- linked to 2H)-pyridine
They differ essentially from the above-mentioned compounds by always containing a purine-2,6-dione and by their specific pharmacological properties.

In the structural formula of the present invention, Atk represents a divalent lower alkyl group; R represents hydrogen, lower alkyl, halo, lower alkyloxy, or hydroxy; the dotted line represents the relationship between the 6- and 4-carbon atoms of the piberison nucleus; Indicates that the double bond is optional,
A novel 1H-indru3 that can be represented by
-yl-containing 1,3-dimethyl-1H-zoline-2,6-
This invention relates to pharmaceutically acceptable acid addition salts of duones and VII.

In the above definitions, the term "halo" generally refers to fluoro, chloro, bromo and iodo; and "lower alkyl" refers to straight and branched saturated hydrocarbon groups having from 1 to 6 carbon atoms; It is meant to include, for example, hamethyl, ethyl, 1-methylethyl, 1.1-trimethylethyl, propyl, butyl, pentyl, hexyl, and the like.

The most preferred compound is 7-1:2-(4-(1#-into-3-yl)-1-piperidinyl]ethyl)-3,
7-dihydro-1,5-methyl-1H-purine-2,
selected from 6-diones and pharmaceutically acceptable acid addition salts thereof.

Compounds of formula (I) can be prepared by reacting intermediates of formula (fl) with biperisone of formula G according to alkylation methods generally known in the art.

H3 In the spring formula (sha) and (e), Ql and Q2 are defined as <, 1.3- in formula (I) during the alkylation reaction.
1-biirisonyl or 3,6-dihydro-1 (2B)-pyridinyl in which dihydro-2,6-dioxo-1,2,3,6-titrahydro-7H-purin-7-yl group is substituted via -Atk- selected to connect to the group. For example, compounds of formula (I) generally have Q! is hydrogen, the intermediate is represented by the formula (m-α), a reagent of the formula σO where Ql represents -A l k-1F', the reagent has the formula (■-α) It can be produced by N-alkylation with .

cH9 (In-α) ----→ (1) In formula (II-a), W is a suitable reactive leaving group, such as halo, such as chloro, bromo or iodo, or a sulfonyloxy group, such as methyl Represents sulfonyloxy or 4-methylphenyl-sulfonyloxy.

In addition, the compound of formula (■) is also a compound of formula (■) in which Ql is hydrogen.
an intermediate of m, the intermediate is represented by formula (n-b),
Q! An intermediate of formula (g) in which is -Ark-IF can be produced by N-alkylating the intermediate with a formula (III-b).

CM.

(I) In formula (IIT-6), W has the meaning defined above.

The alkylation reaction is carried out in an inert organic solvent, such as aromatic hydrocarbons, such as benzene, methylbenzene, trimethylbenzene, etc.; lower alkanols, such as methanol, ethanol, 1-butanol, etc.; y
Lonozanone, 4-methyl-2-pentanone, etc.; Ethers, such as 1,4-soxane, 1,1'-oxybisethane, tetrahydrofuran, etc.: N, N-dimethylformamide (DMF) gN, N-dimethylacetamide ( DMA).

Nitrobenzene; 1-methyl-2-pyrrolisonone; It is advantageously carried out in the same range. To pick up the acid liberated during the reaction, a suitable base such as alkali metal charcoal or bicarbonate, sodium hydride or an organic base such as N
, N-noethylethanamine or #-(1-methylethyl)-2-gulononeamine can be utilized. In such cases, the addition of iodides, preferably alkali metal iodides, is appropriate. The reaction rate can be increased by slightly raising the temperature.

In all the preparations above and below, the reaction products can be isolated from the reaction mixture and, if necessary,
Further purification can be carried out according to methods generally known in the art.

The compounds of formula (I) have basic properties and are therefore suitable for use with suitable acids, such as inorganic acids, such as hydrohalodic acids, such as hydrochloric acid, hydrobromic acid, etc., sulfuric acid, sheath acids, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxy-zolopionic acid, 2-oxopropionic acid, ethansonic acid, grononnsonic acid, putansonic acid, (Z)-2-butenedionic acid, (E)-
2-butenedioic acid, 2-hydroxybutanethoonic acid,
2゜3-nohydroxyptanesonic acid, 2-hydroxy”
/-1t 2 t 3-f Treatment with lopanetricarboxylic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc. and can be converted into its therapeutically active, non-toxic acid addition salt form. Conversely, the salt form can be converted to the free base form by treatment with alkali.

Intermediates and starting materials in the above production can be prepared according to methods known in the art as described, for example, in U.S. Pat. No. 4,064,255, U.S. Pat. .

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are effective antagonists of a range of neurotransmitters, and therefore the compounds have useful pharmacological properties.

For example, compounds of formula (I) and their pharmaceutically acceptable acid addition salts have apomorphine-, tryptamine-, and rubinephrine-antagonistic activity. The activity Vt was verified according to the test method described below, and the experimental data are summarized in Table 1.

Concomitant use of 74 morphine (Al) 0) in rats
, tryptamine (TRY)- and rubinephrine (NOR
) Test The experimental animal used in this test was an adult male Wistar (!i
'1ster) rat (body weight 240±10f). - After an overnight fast, the animals were treated subcutaneously (1 m6/100 t) with an aqueous solution of the test compound (time = 0) and placed in separate observation cages. After 30 minutes (time = 50 minutes), apomorphine hydrochloride CAP : Enthusiasm and cynical chewing. At the end of this hour (time = 90 minutes), the same animal was given tryptamine (TRY).
) 40 μ/kfl was injected intravenously and the presence of typical tributamine-induced bilateral tonic seizures was noted. Two hours after the final pretreatment (time 2120 minutes), the same animals were challenged intravenously with lupinephrine (NOR) 1.25~/klj and possible mortality was determined up to 60 minutes later.

Table 1 shows the EDso values for a number of test compounds.

ED, as used herein. The value is apomorphine-
, represents the dose that protects 50% of the animals from tryptamine- or lupinephrine-induced events.

The compounds listed in the table are not presented for the purpose of limiting the invention, but are intended to illustrate the useful pharmacological activity of all compounds within the second chain.

Because of their pharmacological activity, compounds of formula (I) and their pharmaceutically acceptable acid addition salts are useful for treating psychotropic diseases.
It can be used to treat warm-blooded animals suffering from otropic diseases. This compound also has analgesic and
anti-anxiety (anziolytic), anti-aggressive substance (an
ti-ασσresstva ) and properties useful as anti-stress agents, and thus the compounds are useful for example for the protection of non-human warm-blooded animals under stress situations, such as during transportation periods. More specifically,
The compounds are useful for cattle treatment, minor and major surgery, transportation, and herding.

In view of the usefulness of the compounds in the treatment of psychotropic diseases and their ability to provide analgesic, anxiolytic, anti-aggressive and anti-stress activities, the compounds are formulated into a variety of pharmaceutical forms for administration purposes. be able to.

To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is formulated in intimate admixture with a pharmaceutically acceptable carrier, which carrier is in the desired preparation for administration. It can take a wide variety of forms depending on the form of the object. These pharmaceutical compositions are preferably in unitary dosage forms suitable for oral, rectal or parenteral injection. For example, in preparing compositions in oral dosage forms, common pharmaceutical vehicles such as water, glycols,
Oil, alcohol, etc.: Alternatively, in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, binders, binders, disintegrants, etc. can be used. Because of their ease of administration, traps, tablets, and capsules represent the most advantageous oral dosage forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually consists of sterile water, at least in large part, and may contain other ingredients, eg, to aid solubility. For example, an injectable solution can be prepared, in which case
The carrier consists of a saline solution, a glucose solution or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. It is clear that the acid addition salts of formula (I) are more suitable in the preparation of aqueous compositions due to their increased solubility in water than the corresponding base forms.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used in this specification and the appended claims, dosage unit form refers to physically discrete units suitable for unitary dosage. Contains a predetermined amount of active ingredient calculated to obtain a therapeutic effect. Examples of such dosage unit forms are tablets (scorched or coated), capsules, pills, powder sachets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, etc. The quantity, etc., and the multiple thereof.

The present invention provides a method of treating a warm-blooded animal suffering from the psychotropic disease or a method of treating a warm-blooded animal by providing anxiolytic, anti-aggressive and anti-stress activity. is obvious. The method comprises systemically administering a psychotropically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier.

The appropriate dosage to administer to the patient is 0.001■/9 to 10■/kl of body weight? Weight, more preferably 0.05q/
It ranges from 9 to 9 o, s#9/lv body weight.

The following examples are illustrative of the invention and are not intended to limit the scope of the invention. All parts are parts by weight unless otherwise specified.

Example 1 7-(2-chloroethyl)-3,7-dihydro-1,
5 parts of 3-methyl-1H-purine-2,6-soone, 6
-(4-giberisonyl)-1H-indole 4 parts, sodium carbonate 8 parts, potassium iodide 1 part and 4-methyl-
A mixture of 120 parts of 2-pentanone was stirred and refluxed overnight. The reaction mixture was cooled, water was added and the layers were separated. The mausoleum was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 parts by volume) as eluent.

The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone and 7-r
-2-c4-rlH-indole-3-yl)-1-py4
4 parts of lysonyl]ethyl-3,7-dihydro-1,3-methyl-1H-purine-2゜6-dione (50LX)
Melting point: 2012°C (Compound 1).

Example 2 7-(2-chloroethyl)-3,7-dihydro-1,3
-trimethyl-1H-purine-2,6-noone 3.65 parts, 3-(4-piperidinyl-1H-indole-5-ol 5 parts, sodium carbonate 4.25 parts, potassium iodide 0
．． A mixture of 1 part and 200 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The whole was filtered while hot, and the solution was evaporated.

The remaining age was subjected to MJ in 45 parts of trichloromethane and 2.4 parts of methanol. The product was separated, washed with 16 parts of methanol, and dried to give 3,7-sohydro-7-[2-[
:4-(5-hydroxy-1B-indole-6-yl)
-1-piperidinyl]ethyl]-1,3-tmethyl-1
H-purine-2,.

6-7172.5 parts (4396) was obtained; melting point 232.
5°C (compound 2).

In a similar manner, the following were also produced = 6.7
-dihydro-1,6-nomethyl-7-[2-C4-(7
-Methyl-1H-indo-3-yl)-1-biperisonyl]ethyl)-1H-purine-2,6-dione; melting point 20α2°C (compound 5); 7-(3-(4-(5-fluoro- 1H-indole-5-'fl)-1-1'peridinyl]propyl]-3,7-dihydro-1,5-dimethyl-1H-purine-2,6-dione (A")-2-butenedioate <1:1); melting point 23z3℃ (compound 4
); 7-[2-[4-(5-fluoro-1H-indol-6-yl)-1-piperidinyl]ethyl-5°7-dihydro-1,6-somethyl-1H-purine-2,6-dione; Melting point 16a4°C (compound 5); 7-(3-[4
-(5-chloro-1H-indole31l) -1-hyperisonyl]propyl]-5,7-sihydro1,6-
Cymethyl-1H-purine-2,6-dione; melting point 105
．． 8°C (compound 6); 7-42-44- (5-chloro-1B-indru5
-yl)-1-piperinonyl]ethyl]-5゜7-dihydro-1,3-thumeglu 1H-purine-2,6-dione; melting point 2.25.0°C (compound 7); 3.7-sohydro 7-[-(4-(5-methoxy-I H-indol-3-yl)-1-piperidinyl]ethynoshi]-1,
6-dimethyl-1H-purine-2,6-dione; melting point 2
05.0°C (Compound 8); 6.7-Sohydro7-(3-(4-(5-methoxy-
1H-indolero-yl)-1-biperisonyl]globil':]1,3-tmethyl-1H-purine-2,6-
Zeon; fusion + a? , 1 o a, 4°C a Compound 9)
; 6.7-di and draw 1,3-tmethyl-7-[5-C4
-'(7-methyl-1H-indol-3-yl)-1-
piperidinyl]propyl)-1M-purine-2,6-dione (E)-2-butenedioate (1:1); melting point 2
28.1°C (compound 10); 7-C2-C4-(5-promo1H-indol-5-yl)-3,6-duhydro1 (2/7)-pyrisonyl]ethyl]-3,7-nohydro1゜3-methyl-1H-phosphorus-2,6-
Dione-hydrochloride; melting point 258.9°C (compound 11); and 7-C2-C4-(6-fluoro-1H-indol-3-yl)-3,6-sihydro-1(2H)-viridinyl]ethyl)- 3,7-Sohydro 1°6-nomethyl-1H-purine-2,6-dione; and point 163,5°C (
Compound 12).

Example 3 7-(3-chloroprogyl)-3,7-dihyde t17-
4.5 parts of 1,3-methyl-1H-purine-2,6-dione-hydrochloride, 3 parts of 3-(4-piperidinyl)-1H-indole, 8 parts of sodium carbonate, 0 parts of sodium iodide
．． A mixture of 1 part and 7277240 parts of 4-methyl-2-be was stirred and refluxed for 20 hours. The whole was filtered while hot and the F solution was evaporated. The residue was purified on silica gel with a mixture of trichloromethane and methanol (92:
8 parts by volume) and purified by column chromatography. The pure fractions were collected and the eluent was evaporated. The residue was dissolved in 2-gronozonol (E)-2-
Converted to butenedioate. This salt was taken from house to house, dried, and 6.7-di and 7-[3-[4-(IH7-indol-3-yl)-1-piperidinyl]propyl']-
1,5-dimethyl-1H-purine-2,6-dione (E
)-2-butenedioate (1:1) 3.9 parts (48%
); melting point: 222.7° C. Compound 13) was obtained.

In a similar manner, the following were also prepared:

7-[! 1-[:4- (6-fluoro-1H-indol-3-yl)-1-pid +Jsonyl]glopyr]-
3,7-sihydro-1,6-cymethyl-1H-purine-
2,6-dione; melting point 128.0°C (compound 14); 3.7-sohydro-7-(4-[:4-(IH-indol-3-yl)-1-piperidinyl]butyl]-
1,3-methyl-1H-purine-2,6-dione (E
)-2-butenedioate (2:1)? Melting point 22Z7℃
(Compound 15); and 7-(4-C4-(6-fluoro-1H-indru3)
-yl)-1-speridinyl"butyl]-3,7-dihydro-1,5-tmethyl-1H-gly-2+6-noone; melting point 151.8°C (compound 16).

Example 4 7-('5-chloropronyl)-5,7-dihydro-1
, 5 parts of 3-methyl-1H-purine-2,6-thio/-hydrochloride, 4 parts of 3-(1,2,3,6-tetrahydro-4-pyrisonyl)-1H-indole, 8 parts of sodium carbonate.
A mixture of 1 part and 240 parts of 4-methyl-2-pentanone was stirred at reflux for 22 hours. The whole was stirred until it reached room temperature.

The product was distributed and stirred in water. After Pi, the product was washed with water and an equal amount of acetic acid. The mixture was treated with ammonium hydroxide. The precipitated product is filtered off, washed with water, and stirred in a mixture of acetonitrile and 2-progol. The product was separated, washed with acetonitrile, dried and 2.7-(3-(:3.6-Sihydro4)
7 parts (98%) of -(1#-indole-3-yl)-1(2#)-pyrisonyl]propyl 1-3.7-sihydro-1,3-tmethyl-11-purine-2,6-dione were obtained. ;Melting point 24! L2°C (Compound 17).

In a similar manner, the following were also produced:
4-(3,6-sohydro4-(IH-indru3-
yl)-1(2H)-pyrisonyl]butyl]-3,7-
Sohydro 1,5-methyl-IB-purine-2,6-
dione; melting point 198.3°C (compound 18); and 7-(4-(4-(5-fluoro-1H-indolu3)
-yl)-1-pizonyl]butyl]-3,7-dihydro-1,3-dimethyl-1-purine-2,6-dione (E)-2-butenedioate (1:1) :Melting point 21
0.6°C (Compound 19).

Example 5 7-(3-chloroprobyl)-3,7-dihydro-3-
6 parts of trimethyl-1H-purine-2,6-dione-hydrochloride, 5-promo-3-(1,2,5°6-tetrahydro-
5 parts of 4-pyridinyl)-111-indole-hydrate,
A mixture of 10 parts of sodium carbonate, 0.2 parts of sodium iodide and 165 parts of N,N-dimethylacetamide was stirred overnight and heated to 90°C. The reaction mixture was evaporated to dryness.

7i! 1t7! +: was stirred in water. The product was extracted with trichloromethane. The extract was dried, FJ and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 parts by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was taken from house to house, dried and 7-(3-(4-(5-promo 1H)
-indole-3-yl)-3,6-dihydro-1(2B
)-pyrisonyl]glovir)-3,7-sohydro-11
'5-Methyl-1H-purine-2,6-dione 3.2
(66%); melting point 195.1°C (compound 20)
.

Example 6 7-(2-chloroethyl)-3,7-dihydro-1,3
-trimethyl-1H-purine-2,6-dione 3.8 parts,
3-(3,6-sohydro-1(2H)-pyridinyl)
A mixture of 3 parts of -1H-indole, 8 parts of sodium carbonate, 0.1 part of potassium iodide and 270 parts of methylbenzene was stirred and refluxed for 20 hours. The reaction mixture was filtered hot and the F solution was evaporated. The remaining portion was placed on silica gel,
It was purified by column chromatography using a mixture of trichloromethane and methanol (92:8 parts by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-pronotanone. The product was separated and dried at 120°C under vacuum,
6.7-Sohydro 7-[2-[3,6-Sohydro 4
-(IH-indol-3-yl)-1(2/7)-pyridinyl)ethylj-1,3-tumethyl-1H-zoline-
3.1 parts (51.6%) of 2,6-dione were obtained; melting point 1
96.5°C (Compound 21).

Example 7 3.7-Sohydro-7-(2-[4-(IH-indol-3-yl)-1-piberisonyl]ethyl)-1,3-
Saturated with 5 parts of 2-methyl-1H-purine-2,6-dione, 16 parts of 2-protyanol and hydrogen chloride gas, 2-
The mixture of 160i of pro/9nol was stirred at 70°C for 1 hour. After cooling to 20'C, the product was separated, washed twice with 24 parts of acetonitrile, dried and 3,7-sohydro-7-(2-(4-(1ff-indol-3-yl)-1
-piberisonyl]ethyl]-1,3-tmethyl-1H-
Purine-2,6-dione-hydrochloride 4.3 parts (79rX)
Melting point: 273.0'C (Compound 22).

Example 8 3.7-Sohydro7-42-(4-(1/7-indo-5-yl)-1-piperidinyl]ethyl]-1,3
-tumethyl-1H-zoline-2,6-nooff 5 parts and 2
- 8 parts in a stirred mixture of 100 parts of methoxyethanol
Three parts of 5% phosphoric acid solution were added. After stirring for 60 minutes, the product was separated, washed with 40 parts of methanol, and crystallized from 90 parts of N,N-trimethylborumamide at 0°C. The product was taken from house to house, washed with 16 parts of methanol, dried, and heated to 3°7-
Duhydro-7-[2-(4-(IH-indol-3-yl)-1-t?perisonyl]ethyl]-1,3-dimethyl-1H-purine-2,6-sion phosphate (1:1)
3.4 parts (57%) were obtained; melted at 254.7°C (compound 23).

Following a similar method and using the appropriate acid, the following was also prepared: 3.7-Sohydro7-[:2-(4-(1//-indo-3-yl)-1-piperisonyl]ethyl ]-1,
3-methyl-1-purine-2,6-dione sulfate (1:1): melting point 2557°C (compound 24).

3.7-Sihydro7-[2-(4-(IH-indol-5-yl)-i-piberisonyl]ethyl]-1,3-
Tsumethyl-1H-purine-2,6-dione methanesulfonate; melting point 243.1°C (compound 25).

Example 9 3,7-Sihydro7-C2-C4 in 160 parts of 2-blockol and a small amount of N,N-trimethylformamide
-(1#-indru6-yl)-1-bi4ridinyl]
ethyl]-1,3-methyl-I II-purine-2,
A stirred solution of 5 parts of 6-dione in methanol (
+)-2,3-Sohydroxyptaneson [3.5 parts solution was added.

The whole was stirred under reflux for 60 minutes. After cooling, the product is taken from house to house, dried and (+)-317-sohydro7-(2-
[4-(IH-indol-3-yl)-1-piperidinyl]ethyl)-1,3-dimethyl-1H-purine-2,
6-dione (B-(B*.

R*))-2,3-sohydroxybutanedioe) (
1:1) 6.5 parts (913%) of R64,488 were obtained; melting point 21a2°C (compound 26).

Following a similar method and using the appropriate acid, the following was also prepared: 3.7-Sihydro7-(:2-(4-(1H-indol-6-yl)-1-piperidinyl]ethyl) -1,3
-tumethyl-1H-purine-2,6-dione (Z)-2
-Butennooate (1:1) ij point 166.9°C (
Compound 27).

0 Inventor: Jan van d'Ember Beek, Belgium 0 Inventor: Josef Martin Bieke, Belgium

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, Alk represents a divalent lower alkyl group; R is hydrogen, lower alkyl, halo, lower alkyloxy, or hydroxy The dotted line indicates that the double bond between the 3- and 4-carbon atoms of the piperidine nucleus is optional, and a pharmaceutically acceptable acid addition salt thereof. 2,7-[2-[4-(1H-indol-3-yl)-
1-piperidinyl]ethyl]-3,7-dihydro-1,
A compound selected from the group consisting of 3-dimethyl-1H-purine-2,6-dione and a pharmaceutically acceptable acid addition salt thereof. 3. Suitable pharmaceutical carriers and active ingredients include formulas ▲mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, Alk represents a divalent lower alkyl group; R is hydrogen, lower alkyl, halo, lower represents alkyloxy or hydroxy; the dotted line indicates that the double bond between the 3- and 4-carbon atoms of the piperidine nucleus is optional; analgesic and anxiolytic compounds and pharmaceutically acceptable acid addition salts thereof A psychoactively effective composition having analgesic, anxiolytic, anti-aggressive and anti-stress properties useful in treating non-human warm-blooded animals, comprising an anti-aggressive and anti-stress effective amount. 4, the compound is 7-[2-[4-(1H-indole-3-
yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione and pharmaceutically acceptable acid addition salts thereof. Compositions as described in Section. 5. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, Alk represents a divalent lower alkyl group; R represents hydrogen, lower alkyl, halo, lower alkyloxy, or hydroxy; The dotted line is piperidine An analgesic, anxiolytic, antiaggressive and antistress effective amount of a compound having the following and a pharmaceutically acceptable acid addition salt thereof, in which the double bond between the 5- and 4-carbon atoms of the nucleus is optional. A method of treating a warm-blooded animal other than a human by providing analgesic, anxiolytic, anti-aggressive and anti-stress activity, the method comprising administering systemically to a warm-blooded animal other than humans. 6, the compound is 7-[2-[4-(1H-indole-3-
yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione and pharmaceutically acceptable acid addition salts thereof; The method described in scope item 5. 7. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, Alk represents a divalent lower alkyl group; R represents hydrogen, lower alkyl, halo, lower alkyloxy, or hydroxy; The dotted line is piperidine A method for producing a compound having the formula and a pharmaceutically acceptable acid addition salt thereof, which indicates that the double bond between the 3- and 4-carbon atoms of the nucleus is optional, the method comprising: etc. ▼(II) The intermediate of The expression and Q^2 is hydrogen, or Q^1 is hydrogen and Q^2
represents a group -Alk-W, where W is a reactive leaving group, with the piperidine of and, if necessary, the compound of formula (I) is converted into the therapeutically active non-toxic acid addition salt form by treatment with a suitable acid, or conversely, the acid addition salt form is converted into the therapeutically active non-toxic acid addition salt form. A process characterized in that it is converted into the free base form by means of an alkali; and/or its stereochemical isomers are produced. 8,7-(2-haloethyl)-3,7-dihydro-1,
3-dimethyl-1H-purine-2,6-dione was reacted with 3-(
4-piperidinyl)-1H-indole and, if necessary, the compound thus obtained is converted into the therapeutically active non-toxic acid addition salt form by treatment with a suitable acid, or conversely, 7-[2-[4-(1H
-indol-3-yl)-1-piperidinyl]ethyl]
-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione or a pharmaceutically acceptable acid addition salt thereof.